Diet-derived oxysterols shape intestinal B cell fate by controlling intracellular cholesterol metabolism

饮食来源的氧甾醇通过控制细胞内胆固醇代谢来塑造肠道 B 细胞的命运

基本信息

批准号：
10299176
负责人：
Andrea Reboldi
金额：
$ 46.72万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-25 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10299176
关键词：
16S ribosomal RNA sequencing 25-hydroxycholesterol Adaptive Immune System Antibiotics Antibodies Antibody Formation Antibody Response Antigens Area B Cell Proliferation B cell differentiation B-Cell Activation B-Lymphocytes Bacterial Antigens Bile Acids Binding Proteins Biological Assay Biological Availability Biological Process Cells Cholesterol Cholesterol Homeostasis Clone Cells Communities Complex Couples Cues Data Diet Dietary Cholesterol Dietary Intervention Environment Exposure to Follicular Dendritic Cells Foundations Gastrointestinal tract structure Gene Expression Profile Generations Genes Genetic Transcription Helper-Inducer T-Lymphocyte Homeostasis Immune Immune system Immunology Impairment Individual Intervention Intestines Lead Link Lipids Maintenance Maps Mediating Memory B-Lymphocyte Metabolic Metabolism Modeling Molecular Mus Nature Output Oxides Pathway interactions Peripheral Pharmacology Phenocopy Plasma Cells Play Process Production Reaction Reagent Regulation Response Elements Role Shapes Source Spleen Sterols Stimulus Stromal Cells Structure of germinal center of lymph node Testing Transcriptional Regulation Work adaptive immunity base cholesterol absorption commensal bacteria dietary dietary manipulation draining lymph node expectation in vivo insight intestinal homeostasis lipid biosynthesis lipid metabolism liquid chromatography mass spectrometry lymph nodes machine learning method microbial microbiome microorganism antigen novel oxysterol binding protein plasma cell differentiation prevent response transcription factor transcriptome sequencing

项目摘要

Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by commensals microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody secreting plasma cells or memory B cells. Intestinal B cells are also exposed to dietary and microbial metabolites during their activation and differentiation, but how these environmental cues shape B cell fate and antibody response in the gut is poorly understood. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology. Several lines of evidence indicate that metabolic switches act as intrinsic regulators of germinal center B cell response. However, how B cells integrate metabolite sensing with germinal center and antibody response remains undefined to date. In this application we test the hypothesis that the oxysterol 25-HC, an oxidized form of cholesterol, directly controls germinal center B cell response through its interaction with the Sterol Response Element Binding Protein 2 (SREBP2). SREBP2 is a key regulator of intracellular cholesterol homeostasis, and its transcriptional activity in the intestinal germinal center B cells couples lipid metabolism and B cell differentiation in the intestine. We also hypothesize that follicular dendritic cells (FDCs), stromal cells which are located in the germinal center, produce 25-HC in response to dietary cholesterol and microbiome, therefore linking rapidly changing intestinal homeostasis to B cell fate. Accumulating evidence indicates that 25-HC controls SREBP2 processing, but the implication for this cross talk in B cells in the gut has not been investigated so far. Our aims are: 1) To test the hypothesis that SREBP2 activity controls germinal center B cell transcriptional profile and B cell fate; and 2) To define the environmental and cellular cues that regulate 25-HC niche. The proposed studies examine a very poorly understood crosstalk between oxidized form of cholesterol, intestinal metabolism and adaptive immune system activation. It is our expectation that these studies will increase our understanding of how intestinal metabolism shapes B cell responses and adaptive immunity. Furthermore, these studies will provide a foundation for better understanding of the relationship between lipid metabolism and differentiation in immune cells.

抽象的胃肠道中的 B 淋巴细胞不断受到共生微生物抗原的刺激。为了为了防止共生生长并维持肠道稳态，B 细胞需要快速产生抗体反应针对细菌抗原。为了实现这一任务，体液免疫系统依赖于 B 细胞增殖和增殖的复杂多步骤过程。生发中心的选择，最终产生分泌抗体的浆细胞或记忆 B 细胞。肠道 B 细胞在激活和分化过程中也会接触饮食和微生物代谢物，但是这些环境因素如何影响肠道中 B 细胞的命运和抗体反应，人们知之甚少。因此，阐明内在调节个体 B 细胞命运和功能的基本机制肠道中的克隆仍然是免疫学的一个中心问题。多项证据表明代谢开关是生发中心 B 细胞反应的内在调节因子。然而，B 细胞如何将代谢物传感与生发中心和抗体反应结合起来仍不清楚日期。在此应用中，我们测试了以下假设：氧化型胆固醇 25-HC 直接控制生发中心 B 细胞通过其与甾醇反应元件结合蛋白 2 (SREBP2) 的相互作用做出反应。 SREBP2 是细胞内胆固醇稳态的关键调节因子，其在肠道中的转录活性生发中心 B 细胞将肠道中的脂质代谢和 B 细胞分化结合起来。我们还假设滤泡树突状细胞 (FDC) 是位于生发中心的基质细胞，可产生 25-HC 以响应膳食胆固醇和微生物组，因此将快速变化的肠道稳态与 B 细胞的命运联系起来。越来越多的证据表明 25-HC 控制 SREBP2 加工，但 B 中这种串扰的含义迄今为止，尚未对肠道细胞进行研究。我们的目标是：1) 检验 SREBP2 活性控制生发中心 B 细胞转录谱的假设，以及 B细胞命运； 2) 定义调节 25-HC 生态位的环境和细胞线索。拟议的研究检查了氧化形式的胆固醇、肠道胆固醇之间的串扰，这一点我们知之甚少。新陈代谢和适应性免疫系统激活。我们期望这些研究将增加我们的了解肠道代谢如何影响 B 细胞反应和适应性免疫。此外，这些研究将为更好地理解脂质代谢与分化之间的关系提供基础免疫细胞。